JPH06505567A - Blood thrombolytic activity measurement method - Google Patents
Blood thrombolytic activity measurement methodInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/49—Blood
- G01N33/4905—Determining clotting time of blood
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Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 血液の血栓熔解活性測定法 本発明は、血液(全血)の血栓溶解活性を試験管内で測定する方法に関するもの で、特に生体内に擬した条件下で、試験管内に作った閉塞性の血小板血栓の崩壊 を測定する方法、ならびにその実施に必要な装置に関するものである。[Detailed description of the invention] Blood clot-dissolving activity measurement method The present invention relates to a method for measuring thrombolytic activity of blood (whole blood) in vitro. In particular, the disruption of occlusive platelet thrombi created in vitro under conditions simulating in vivo conditions. It relates to a method for measuring , as well as the equipment necessary for its implementation.
血液の血栓溶解活性を測定できるということは非常に重要なことである。例えば 、血栓の自然崩壊が起こるか否かは、患者が急性心筋梗塞を切り抜けられるが否 かに関わる主要な決定要因の一つである(Swan H,J、C,Acute Myocardial Infarction : A failure to timely、5pontaneous thrombolysis、Tou rnal 盾■@A11er jean CoCo11e of Cardiclogy 13:1435−3 7(1989))、また心肺バイパス手術中に起こり得る血栓の過剰崩壊が、手 術成功後の重篤な出血の主要な原因になると考えられている。It is of great importance to be able to measure the thrombolytic activity of blood. for example Whether or not the blood clot spontaneously disintegrates depends on whether the patient can survive an acute myocardial infarction or not. (Swan H, J, C, Acute) Myocardial Infarction: A failure to timely, 5pontaneous thrombolysis, Tou rnal shield ■@A11er jean CoCo11e of Cardiology 13:1435-3 7 (1989)), and excessive disruption of blood clots that can occur during cardiopulmonary bypass surgery It is thought to be a major cause of severe bleeding after successful surgery.
さらに、生命を脅かす動脈血栓症に対して、血栓溶解療法、例えば自然の血栓崩 壊に類似する組織プラスミノゲン・アクチベータ(t−PA)やストレプトキナ ーゼによる治療は現在量も有効なものである。血栓溶解療法の有効率(再開通率 )や、出血等の副作用は投与量に比例する。また多数の要因により、個々の患者 に必要な血栓溶解剤の投与量は大きく異なる。したがって、治療効果を迅速に手 早くモニターできる技術が必要となってくる。In addition, for life-threatening arterial thrombosis, thrombolytic therapy, such as natural thrombolysis, is recommended. tissue plasminogen activator (t-PA) and streptokina The current dose of treatment with this enzyme is also effective. Effective rate of thrombolytic therapy (recanalization rate ) and side effects such as bleeding are proportional to the dose. Many factors also affect individual patient The doses of thrombolytic agents required vary widely. Therefore, the therapeutic effect can be quickly accessed. Technology that can quickly monitor the situation will be needed.
線溶(線維素溶解)系の測定は数多く知られている。しかし全血漿や全血ニーグ ロブリンやフィブリノーゲン等の血漿蛋白の崩壊時間のような総合的な線溶系の 分析は面倒で時間もかかり、臨床的には稀にしか実施されない。線溶状態の評価 は、通常その因子を手掛かりとして行われるが、実施にあたっては少なくとも6 つ以上の変数が測定される。その評価に必要とされる変数の数は常に増加してい るが、個々の変数から全体の状況を読みとることは極めて困難である。Many measurements of the fibrinolytic (fibrinolytic) system are known. But whole plasma or whole blood of the overall fibrinolytic system, such as the decay time of plasma proteins such as lobulin and fibrinogen. The analysis is tedious, time-consuming, and rarely performed clinically. Evaluation of fibrinolytic state is usually carried out using the factors as clues, but at least 6 More than one variable is measured. The number of variables required for its evaluation is constantly increasing. However, it is extremely difficult to interpret the overall situation from individual variables.
線溶系と異なり、臨床用の血栓崩壊測定法は開発されていない。動脈血栓はほと んどが血小板であるが、白血球も多少混じった固い凝塊であり、その崩壊は基本 的に線溶系とは異なる。血小板より放出される抑制物質により、血栓は血餅より も崩壊に対する抵抗性が強い。Unlike the fibrinolytic system, a clinical method for measuring thrombolysis has not been developed. Arterial thrombosis is rare Most of them are platelets, but they are hard clots with some white blood cells mixed in, and their disintegration is a basic process. It is different from the fibrinolytic type. Due to inhibitory substances released by platelets, blood clots are prevented from forming. It is also highly resistant to collapse.
試験管内で血栓の崩壊を観察、測定するためには、まず血栓を作らなければなら ない、測定を有意義なものとするには、すなわち生体内と正確に同じようにする には、血栓を生理学的な方法で作成しなければならない、その条件は当然、生体 内で見られることを正確に再現することである。特に血栓の形成開始に関与する 最も重要な因子の一つは、血行力学的な力である剪断刺激(shear 5tr ess)である、血栓の形成中にトロンビンができるが、このトロンビンは剪断 力(shearforces)と相まって決定的な役割を演する。トロンビンは 血小板凝集を増強し、フィブリンを形成することによって、血栓を構造的に安定 なものにする。In order to observe and measure the disintegration of a blood clot in a test tube, a blood clot must first be created. No, for the measurements to be meaningful, i.e. exactly as they would be in vivo. For this purpose, blood clots must be created in a physiological manner, and the conditions for this must naturally be The aim is to accurately reproduce what is seen inside. Particularly involved in the initiation of blood clot formation One of the most important factors is shear stimulation, which is a hemodynamic force. thrombin is produced during thrombus formation, which is Together with shear forces, it plays a decisive role. Thrombin is Structurally stabilizes blood clots by enhancing platelet aggregation and forming fibrin Make it something.
したがって、生理学的に適切な方法で血栓を作成するには、抗凝血剤添加血液の 中では血栓はできないので、抗凝血薬無添加の血液試料を用いるべきである。Therefore, to create a blood clot in a physiologically relevant manner, anticoagulated blood must be Blood samples without anticoagulants should be used because blood clots cannot form in the blood.
また血栓の形成は完全に剪断力のみで開始されるようにすべきで、ほかに血栓の 形成を刺激するようなものがあると、テストは生理学的にまったく見当違いのも のになってしまう。In addition, thrombus formation should be initiated entirely by shear force; If there is something that stimulates formation, the test may be completely misplaced physiologically. It becomes .
出願人の知る限り、血栓崩壊測定法として知られているのは、欧州特許出aO1 29425と、国際特許出願PCT/GB87100633の2つのみである、 これらの出願明細書の中に記載されている方法では、血栓は、血液が還流するポ リエチレン製のチューブにあけられた小さな孔の中に形成される。血液中の血栓 の状態は、チューブの中の血流の停止と血栓の除去、結果として血流の再開とし て観察、測定される。To the applicant's knowledge, the only known thrombolytic assay is the European patent aO1. 29425 and international patent application PCT/GB87100633. In the methods described in these applications, the thrombus is It is formed in a small hole in a polyethylene tube. blood clot This condition involves stopping the blood flow in the tube, removing the blood clot, and eventually restarting the blood flow. observed and measured.
これら明細書に記載の方法は、前述の規準を満たすものではあるが、しかし本質 的な欠点が多々ある。中でもことに重大なものは、血液を還流し、血栓を作るチ ューブの中で、血栓の前後に血餅ができることである。すなわち血栓を除去する ために圧力を逆転させた時、その圧力の伝わり方が、血餅の抵抗により阻害され たり、あるいは大きく妨害される。したがって血栓にかかる圧力が、一定でなく 、変わりやすいということになる。Although the methods described in these specifications meet the aforementioned criteria, There are many shortcomings. Among these, the most important one is the circulation of blood and the formation of blood clots. Blood clots form in the tube before and after the blood clot. i.e. remove blood clots When the pressure is reversed for this purpose, the way the pressure is transmitted is inhibited by the resistance of the blood clot. or be seriously interfered with. Therefore, the pressure applied to the thrombus is not constant. , which means that it is easy to change.
また、ポリエチレンと血栓塊の相互作用が弱い。したがって部分的に固まった血 液が間歇的に動く結果、一旦凝血が起こると還流圧が変化し、実際の崩壊ではな くて、脆い血栓が除去されてしまうというようなことが起こる。このため、血栓 の崩壊を適切な方法で、かつ再現性をもってモニターすることはできないという 結果となる。In addition, the interaction between polyethylene and the thrombus is weak. therefore partially clotted blood As a result of the intermittent movement of the fluid, once clotting occurs, the reflux pressure changes, preventing actual collapse. This may result in the removal of a fragile blood clot. For this reason, blood clots It is not possible to monitor the decay in a suitable manner and reproducibly. result.
またこれまでの方法のもう一つの欠点として、血栓は生体内に比べて、試験管内 では一層崩壊しにくいということが挙げられる。これは主として、循環を除けば 、血栓崩壊の重要な決定因子である組織プラスミノゲン・アクチベータ(1−P A)が極めて速やかに分解され、不活化されることによる。もし血栓を速やかに 作ることができれば、t−PAは速やかに血栓に結合するので、その分解を防ぐ ことができる。しかしながら、今までに報告されている方法では、患者からの採 血から、分析開始、血栓形成までに数分かかり、この間に血漿中のt−PA濃度 は、検出可能な血栓崩壊に必要なレベル以下に低下してしまう。Another drawback of conventional methods is that blood clots occur in vitro compared to in vivo. This means that it is even more difficult to collapse. This is mainly due to the fact that, apart from circulation, , tissue plasminogen activator (1-P), an important determinant of clot breakdown. This is because A) is extremely rapidly decomposed and inactivated. If a blood clot occurs immediately If t-PA can be produced, it will quickly bind to blood clots and prevent their breakdown. be able to. However, in the methods reported so far, It takes several minutes for analysis to start and clot formation from blood, and during this time the t-PA concentration in plasma increases. decreases below the level required for detectable clot disruption.
本発明の目的は、生理的に適切な、調整された条件下で形成された血小板血栓の 崩壊を測定する、適切、正確、簡単な方法を提供することにある。The purpose of the present invention is to eliminate platelet thrombi formed under physiologically relevant and controlled conditions. The objective is to provide a suitable, accurate and simple method of measuring decay.
発明の一つの態様は、閉塞性の血栓形成方法が、その抗凝血薬を添加しない試料 の供給元から毛細管を通して貯蔵槽に血液を圧力下で流して、その結果剪断刺激 のみで毛細管内に血栓が形成されるように血液を流すこと、血栓形成を検出する こと、圧力を低下させること、および、あらかじめ定めである時間中その圧力を 維持すること、から構成されていることにある。In one aspect of the invention, the method for forming an occlusive thrombus can be performed on a sample without the addition of an anticoagulant. blood flows under pressure from a source through a capillary tube into a reservoir, resulting in a shear stimulus Detect thrombus formation by flowing blood so that a thrombus forms within the capillary to reduce the pressure, and to maintain that pressure for a predetermined period of time. To maintain, to consist of.
上記の態様に沿って、装置は、抗凝血薬非添加血液の供給元、圧力下で毛細管を 通り、貯蔵槽に至る血液の流れを作る手段、毛細管内に形成される血栓を検出す る手段、そしてそれを検出したら圧力を低下させる手段によって構成される。In line with the above embodiments, the device provides a source of non-anticoagulated blood, a capillary tube under pressure. Detect blood clots that form in capillaries and means to reduce the pressure when it is detected.
この装置の利点は、血栓が抗凝血薬非添加血液から剪断刺激のみによって作られ る、すなわち血栓形成が生理学的に適切な方法で行われるということである。The advantage of this device is that blood clots are created from non-anticoagulated blood only by shear stimulation. This means that thrombus formation occurs in a physiologically relevant manner.
さらに、血栓形成後は圧力を低下させることで血栓を安定化し、生体内の自然な 血栓と正確に同じものができるように考案されており、このため試験の結果は一 層有意義なものとなっている。Furthermore, after clot formation, the blood clot is stabilized by lowering the pressure, and the natural in-vivo It is designed to produce exactly the same thing as a blood clot, so the test results are not the same. It has become even more meaningful.
この発明のもう一つの態様は、閉塞性血栓の崩壊を観察、測定する方法が、試料 として抗凝血薬を添加しない血液を毛細管に流すことにより毛細管内の血栓を形 成すること、また同一試料に今度は抗凝血薬を添加した血液を供給する毛細管を 接続すること、抗凝血薬添加血液で血栓に圧力をかけること、および、血栓の崩 壊を検出することといった要素で構成されていることにある。Another aspect of the present invention is that the method for observing and measuring the disintegration of an occlusive thrombus includes Blood clots in the capillaries are formed by flowing blood without anticoagulants into the capillaries. and a capillary tube that supplies the same sample with blood spiked with an anticoagulant. connecting, applying pressure to the clot with anticoagulant blood, and disintegrating the clot. It consists of elements such as detecting damage.
上記の態様に沿って、装置は、抗凝血薬非添加血液の供給元、毛細管内に血栓を 作るために血液を毛細管を通して貯蔵槽に流す手段(この血液は、貯蔵槽で抗凝 血薬と混合される)、血流の方向を逆転させる手段、そして血栓の崩壊を検出す る手段によって構成されている。In line with the above aspects, the device includes a source of non-anticoagulated blood, which deposits a blood clot within a capillary tube. A method of flowing blood through a capillary tube into a storage tank for production (this blood is anticoagulated in the storage tank) (mixed with blood drugs), a means of reversing the direction of blood flow, and detecting the disintegration of blood clots. It is constructed by means of
この態様で重要な特徴は、血栓形成部位を通過した直後に血液を抗凝血薬と混合 することである。そうすれば、血栓ならびに血栓形成過程のいずれもが抗凝血薬 の影響を受けずにすみ、さらに抗凝血薬非添加血液から血栓が作られる間、末梢 に送られた血液は凝血から守られ、その結果試験の間中、液状に保たれる。これ によって末梢血により血栓にかかる圧力が平均した十分なものであることが確実 となる。An important feature of this embodiment is that the blood is mixed with an anticoagulant immediately after passing through the site of thrombus formation. It is to be. In this way, both the blood clot and the blood clot formation process can be prevented by the anticoagulant. In addition, while blood clots are formed from blood without anticoagulants, peripheral The blood sent to the test tube is protected from clotting and thus remains liquid throughout the test. this to ensure that the pressure exerted on the clot by the peripheral blood is average and sufficient. becomes.
特に好ましい実施例においては、毛細管が血栓形成に通した素材で作られており 、とくにポリエーテルエーテルケトン(polyetheretherketo ne、PEEK)で、比較的長い、15g++s<らいで作られている。これに よって毛細管腔によく接着する細長い血栓ができ、それが圧縮されると、例えば 300 mmm1(以上の圧力に対しても砕けたり、移動したりすることなく耐 えられるものとなる。このような血栓の移動は特定の崩壊過程によってのみ起こ るものであり、毛細管の素材やその長さにより、従来の方法に用いられている毛 細管より、より早く血栓を形成させることができる。In particularly preferred embodiments, the capillary tube is made of a material that is permeable to thrombus formation. , especially polyetheretherketone ne, PEEK), relatively long, and made of 15g++s<2. to this This creates an elongated thrombus that adheres well to the capillary lumen, and when compressed, e.g. 300 mm1 (withstands pressure of over 300 mm without breaking or moving) It becomes something that can be earned. This movement of thrombus occurs only through a specific disintegration process. However, depending on the material and length of the capillary, the capillary used in the conventional method is Thrombi can form more quickly than tubules.
特に血流を反転させる手段を採用したので、比較的簡単な装置となり、その結果 この血栓崩壊分析法は容易に自動化でき、操作も簡単となった。多数例の評価に も適するものである。In particular, the use of a means of reversing blood flow results in a relatively simple device; This thrombolytic analysis method can be easily automated and is simple to operate. For evaluation of multiple cases is also suitable.
この装置は、貯蔵槽の本体と、2つの入口と1つの出口から構成される0毛細管 は最初の入口に取りつけら娠その一部は貯蔵槽の中に突き出ているようにする。This device consists of a storage tank body and a 0 capillary tube consisting of two inlets and one outlet. is attached to the first inlet so that part of it protrudes into the reservoir.
2番目の入口には、貯蔵槽の中に一定量の抗凝血薬を供給する装置をつなぐ貯蔵 槽の出口は補助の貯蔵槽と導管で結んでおくことが望ましく、またこの導管の中 の血液の稀釈をモニターするために、光センサーあるいはその他の検出装置を準 備する。この装置で驕者は血栓形成ならびに血栓崩壊の両方を検出することがで きる。一つの検出装置ですむということは、単純化の上で、また経費の上で利点 であり、またこの装置の自動化を容易なものとしている。The second inlet has a reservoir that connects a device that supplies a fixed amount of anticoagulant into the reservoir. It is desirable to connect the outlet of the tank to the auxiliary storage tank with a conduit, and the inside of this conduit should be Prepare an optical sensor or other detection device to monitor the dilution of the blood. Prepare. With this device, the company is able to detect both clot formation as well as clot disintegration. Wear. Requiring only one detection device has advantages in terms of simplicity and cost. This also makes the device easy to automate.
血液を流す手段は、貯蔵槽と毛細管に圧力をかけることのできるポンプで構成さ れ、更にこれらに加えて第2貯蔵槽とその連結導管で構成することができる。The means of blood flow consists of a reservoir and a pump capable of applying pressure to the capillary tube. Furthermore, in addition to these, it can be constructed of a second storage tank and its connecting conduit.
ポンプは陽圧、陰圧、ならびに大気圧を供給できるものが好ましい。Preferably, the pump is capable of supplying positive pressure, negative pressure, and atmospheric pressure.
以下、本発明について、本発明に係る装置の断面を示す添付図面を参照しつつ実 施例により詳しく説明する。Hereinafter, the present invention will be explained in detail with reference to the attached drawings showing a cross section of the device according to the present invention. This will be explained in detail with reference to examples.
図中の本体2には、中央室4と、2つの人口6と8がある。本体2は第1の入口 6の上まで伸びていて、雄型1eurの形をした延長部9には拡大した中央溝1 0が納められている0毛細管12は中央溝10の中にシリコンゴムの栓13で支 えられている0毛細管12の上部先端は延長部9の先端と揃えらL一方下部先端 は中央室4の中に突出して、第2の入口8と同じ高さに揃えるか、さらに下まで 突き出ている。The main body 2 in the figure has a central chamber 4 and two ports 6 and 8. Main body 2 is the first entrance 6 and has an enlarged central groove 1 in the male-shaped extension 9. The 0 capillary tube 12 containing 0 is supported in the central groove 10 with a silicone rubber stopper 13. The upper tip of the capillary tube 12 is aligned with the tip of the extension 9, while the lower tip is aligned with the tip of the extension 9. protrudes into the central chamber 4 and is flush with the second inlet 8 or even further down. It sticks out.
本体2には第2の入口8と微量定量ポンプ(図示せず)についているプラス子イ ンクチューブ18を結ぶ導管16のある翼14がある。この微量定量ポンプは、 抗凝血薬を一定比率で、例えば100μ/wit、で中央室4に供給するための ものである。The main body 2 has a second inlet 8 and a phillips head attached to a micrometer metering pump (not shown). There is a wing 14 with a conduit 16 connecting the tank tubes 18. This micro metering pump is for supplying an anticoagulant at a constant rate, for example 100μ/wit, to the central chamber 4; It is something.
毛細管12はIC1社製のポリエーテルエーテルケトン(PEEK)で作られた ものが大変適しており、その寸法は、外径が1.6關、内径0.125關から0 .175+nの間で、長さは10〜20+m、好ましい長さは15m−である、 PEEKチューブは、毛細管の内部を歪めることなく、刃物で容易に好みの長さ に切ることができる。PEEKは化学的に活性ではないが、この表面に活性血小 板が付着する。Capillary tube 12 was made of polyetheretherketone (PEEK) manufactured by IC1. It is very suitable, and its dimensions are 1.6 mm in outer diameter and 0.125 mm in inner diameter. .. 175+n, the length is 10-20+m, the preferred length is 15m- The PEEK tube can be easily cut to the desired length with a knife without distorting the inside of the capillary. It can be cut into Although PEEK is not chemically active, it does contain active blood particles on its surface. The board will stick.
本体2の上端には雄型1eur取りつけ具の形になっている延長部9があり、血 液容器となる一定の長さのポリエチレンチューブ20が取りつけられている。チ ューブ20の上端は雌型1eurを取りつけるようになっていて、これに注射筒 を接続できるようになっている。At the upper end of the body 2 there is an extension 9 in the form of a male 1eur fitting, which A polyethylene tube 20 of a certain length is attached to serve as a liquid container. blood The upper end of the tube 20 is designed to attach a female type 1 euro, and a syringe is attached to this. It is now possible to connect.
本体2の下端は雌型1eur22が取りつけられる形になっている。混合室4は 栓状物26の上についたシリコンゴムチューブ24で密閉されているが、この部 分の上端は雄型1eurを取りつける形になっていて、雌型1eur22で受け られている。赤外線源と集積型光検出器からなる光センサ−ユニット28は栓状 物26の下部に組込まれている。プラスチックの連結導管30がチューブ24と 栓状物26を貫いて貯蔵槽32の中にまで伸びている。この導管30は光センサ −ユニットの中央を通っている。貯蔵槽32はプラスチックの容器33とネジで 取りつけられた金属の蓋34でできており、この二つで内部を密封するためにゴ ム製の0(オー)リング36が用いられている。134には取りつけ具38がつ いていて、導管30と容器33の間の密封に役立っている。The lower end of the main body 2 has a shape to which a female mold 1eur22 can be attached. Mixing chamber 4 It is sealed with a silicone rubber tube 24 attached to the top of the plug 26, but this part The upper end of the minute is shaped to attach the male type 1 euro, and the female type 1 euro 22 is received. It is being The optical sensor unit 28 consisting of an infrared source and an integrated photodetector is plug-shaped. It is incorporated in the lower part of the object 26. A plastic connecting conduit 30 connects to the tube 24. It extends through the plug 26 and into the storage tank 32 . This conduit 30 is a light sensor - Passes through the center of the unit. The storage tank 32 is connected with a plastic container 33 and screws. It is made up of a metal lid 34 attached to it, and the two are made of rubber to seal the interior. An 0 (O) ring 36 made of aluminum is used. 134 has a fitting 38. This serves to provide a seal between the conduit 30 and the container 33.
蓋34には連結導管40がついており、これにポンプを取りつけて、その弁を作 動させることによって、貯蔵槽32、導管30、中央室4および毛細管12を陰 圧、大気圧および陽圧にすることができる。A connecting conduit 40 is attached to the lid 34, to which a pump is attached and its valve is created. By moving the reservoir 32, the conduit 30, the central chamber 4 and the capillary tube 12 pressure, atmospheric pressure and positive pressure.
血液資料の血栓溶解活性は次の3つの段階を経て測定される。第1に毛細管の管 腔に血栓をつ(す、第2に血栓を安定化し、第3にその血栓を圧力をかけて除去 する。Thrombolytic activity of blood samples is measured through three steps: Firstly, the capillary tube The second step is to stabilize the thrombus, and the third step is to apply pressure to remove the thrombus. do.
試験用の血液試料は静脈から採取されるが、これは2筒弐の使用が好ましい。Blood samples for testing are taken intravenously, preferably in two tubes.
針やプラスチックチューブとの接触で汚染された最初の血液1〜2mlは廃棄す るか、通常の血液検査に用いる。次いで血液試料の入った注射器をチューブ20 に接続する。The first 1-2 ml of blood contaminated by contact with the needle or plastic tube should be discarded. or for regular blood tests. The syringe containing the blood sample is then inserted into tube 20. Connect to.
注射器の内筒をゆっくり動かして血液をチューブ20に押し出すが、この時毛細 管12の上端と、血液のカラムの間に10mm程度のエアギャップを残しておく 、この操作中、装置を開放しその内部は大気圧としておく。Move the inner barrel of the syringe slowly to push the blood into the tube 20, but at this time the capillary Leave an air gap of about 10 mm between the upper end of tube 12 and the blood column. During this operation, the device is opened and its interior is kept at atmospheric pressure.
分析は装置を陰圧にすると同時に始まり、微量定量ポンプも作動し始める。Analysis begins as soon as the device is brought to negative pressure, and the micro-metering pump also begins to operate.
真空にすると、血液容器チューブ20の中の血液は毛細管を通って波板入口8か ら入る抗凝血薬と混合する中央室4に入る。抗凝血薬が添加された血液は導管3 0を通って貯蔵槽32に流れこむ、この時点の血液の経路を矢印で示した。When a vacuum is applied, the blood in the blood container tube 20 passes through the capillary tube and enters the corrugated plate inlet 8. The blood enters the central chamber 4 where it is mixed with anticoagulant. Blood with anticoagulant added is in conduit 3 The path of the blood at this point, flowing into the storage tank 32 through 0, is indicated by an arrow.
血液が毛細管12の中に入ると同時に、注射器を血液容器チューブ2oがらはず す。As soon as the blood enters the capillary tube 12, remove the syringe from the blood container tube 2o. vinegar.
真空になると、直ちに、あるいはごく短時間、例えば5秒後には光センサ−2日 が作動し始める。この装置は、導管30の中の毎秒あたりの移送量を検出する、 ひとたび分析が始まると、導管30に血液が流れるため、その色は暗色に変わる 。When a vacuum is created, the light sensor is activated immediately or after a very short time, e.g. 5 seconds. starts working. The device detects the amount transferred per second within the conduit 30. Once the analysis begins, the color changes to a darker color as blood flows through the conduit 30. .
血栓形成の課程は、血小板の凝集とほとんど同時に毛細管12の中で始まり、そ の中に血栓が形成される。毛細管腔の閉塞が増すにつれて、流れる血液の量は減 少する。抗凝血薬の注入速度は一定であり、導管30を通って流れ出る抗凝血薬 添加血液は結局色の薄い、または透きとおった感じとなる。導管30を通って流 れ出る血液の稀釈度は、毛細管腔の閉塞の程度を直接示すものである。光センサ −ユニット2日は、毛細管腔の約90%が閉塞した時に見られる稀釈度を検出す るように設定しである。The process of thrombus formation begins within the capillary tube 12 almost simultaneously with platelet aggregation; A blood clot forms within the . As the occlusion of the capillary lumen increases, the amount of blood flowing decreases. Do a little. The infusion rate of anticoagulant is constant and the anticoagulant flowing through conduit 30 The added blood ends up appearing pale or transparent. Flow through conduit 30 The dilution of the blood that escapes is a direct indication of the degree of occlusion of the capillary lumen. light sensor - Unit 2 detects the degree of dilution seen when approximately 90% of the capillary lumen is occluded. It is set so that
特定の稀釈度を検出した時、光センサーユニット28は信号を制御手段(図示せ ず)に発して真空を解除するポンプを作動させ、装置の内部を約15分間大気圧 下におくようにする。システムが大気圧下にある間に、血小板凝集の十分でない 不安定な血栓は、網の目状に絡んだ血小板周囲の血栓内部にフィブリンのネット ワークが形成され、また相互に交差結合して構造的に安定化する。When a particular dilution is detected, the optical sensor unit 28 sends a signal to the control means (not shown). Activate the pump that releases the vacuum at Make sure to put it down. Insufficient platelet aggregation while the system is under atmospheric pressure An unstable thrombus is a network of fibrin inside the thrombus surrounding the platelets. Workpieces are formed and cross-linked to each other and structurally stabilized.
血栓の安定化が進む間に、連結導管30内の稀釈された血液中の血液細胞は沈澱 する。その結果光センサ−ユニット28の監視する部分はより透明となり、貯蔵 槽32の中に突出している導管の下端は沈澱した赤血球細胞で暗色を呈する。While stabilization of the thrombus progresses, blood cells in the diluted blood within the connecting conduit 30 precipitate. do. As a result, the part monitored by the optical sensor unit 28 becomes more transparent and the storage The lower end of the conduit, which projects into the bath 32, is dark in color with precipitated red blood cells.
安定化の段階が終了すると、制御手段はポンプに貯蔵槽32を陽圧にするように 働く、この場合の圧力は、太い動脈の圧力である150+nHg<らいが望まし い、圧力をかけると血栓塊は圧縮されて、反対側からの圧力にも耐えられるよう になり、毛細管12を通した人工的な漏出は起こらない0次に毛細管腔の血栓の 崩壊が起こる。血栓が崩壊すると、中央室4の中の、稀釈されて細胞の存在しな い血漿が毛細管12を流ね、導管30の中の血漿はシステムの圧力で上方に移動 する。導管内の血液の下の部分、前述の赤血球の沈澱で暗色を呈している部分が 光路に入り、光センサ−ユニット28によって検出される。光センサ−ユニット 28は、血栓の崩壊が起こったこと、および、分析が終了したことを知らせる。Once the stabilization phase is complete, the control means causes the pump to bring the reservoir 32 to positive pressure. The working pressure in this case is preferably 150 + nHg, which is the pressure of a large artery. When pressure is applied, the clot is compressed so that it can withstand pressure from the opposite side. Therefore, no artificial leakage through the capillary tube 12 occurs, and the thrombus in the capillary lumen is A collapse occurs. When the thrombus disintegrates, the central chamber 4 becomes diluted and free of cells. The plasma flows through the capillary tube 12 and the plasma in the conduit 30 is moved upward by the pressure of the system. do. The lower part of the blood in the duct, the part that is dark due to the sedimentation of red blood cells mentioned above, The light enters the optical path and is detected by the optical sensor unit 28. optical sensor unit 28 signals that the thrombus disruption has occurred and that the analysis is complete.
この時点で制御ユニットはチューブ20からの血液の漏出を防ぐために、システ ムを大気圧下におくように働(。At this point, the control unit has activated the system to prevent blood from leaking out of the tube 20. work to keep the chamber under atmospheric pressure (.
この装置は完全自動化することができる。検者は単に血液容器2oに試料を人ね 、制御手段を作動させて注射器を取りはずすだけでよい、その後は制御手段が各 段階を自動的に実施するので、他にすることはまったくない。テストパラメータ ー、特に血栓の崩壊が起こるまでの時間は自動的に記載さ娠保管される。テスト 終了時点で、この装置は血液による汚染の危険なしに、安全に廃棄できる。This device can be fully automated. The examiner simply places the sample into blood container 2. , it is only necessary to activate the control means and remove the syringe, after which the control means The steps are performed automatically, so there is nothing else to do. test parameters - In particular, the time until the breakdown of the blood clot occurs is automatically recorded and stored. test At the end, the device can be safely disposed of without risk of blood contamination.
従って、この装置によれば最小の人員で試験を行うことができる。さらにこの装 置は、例えば多数の系統を設定して、別々に作動させるが、全体を一つの制御手 段でコントロールするなど、複式の形で特に効果的に使用することができる。Therefore, this device allows testing to be performed with a minimum number of personnel. Furthermore, this outfit For example, many systems can be set up and operated separately, but the whole system can be controlled by one control hand. It can be used particularly effectively in a compound form, such as when controlled in stages.
この装置はまたいろいろに使うことができる。第1に、本体を反転させることが できる。そうすると血栓を形成する血液は毛細管12を通って上方に流れる。This device can also be used in a variety of ways. First, it is possible to invert the main body. can. The blood forming the thrombus then flows upward through the capillary tube 12.
血液は毛細管12の周囲の中央室4の中で抗凝血薬と混合される。そして貯蔵槽 と中央室の接続に対して圧力をかけると、血液が貯蔵槽に吸い上げられる。次い で血液は、毛細管12を血液の供給元から切り離すと共に、毛細管12を光検出 器が備えられている排出ラインに再接続した後に、中央室に戻される。The blood is mixed with anticoagulant in the central chamber 4 around the capillary tube 12. and storage tank When pressure is applied to the connection between the central chamber and the central chamber, blood is drawn up into the reservoir. next The blood is separated from the capillary tube 12 from the blood supply source and the capillary tube 12 is detected by optical detection. After reconnecting to the discharge line where the container is provided, it is returned to the central chamber.
崩壊までの時間を測定すべき血栓は、単一で、はっきりした、生理学的に適切な 刺激、すなわち血行動態学的圧力(剪断力、5hear force)によって 、抗凝血薬非添加血液から作られる。この血栓は十分に強固で、動脈血圧に近い 圧力にも耐えて引き離されることはないが、むしろ自然に崩壊する。血栓の形成 は血液試料開始後すぐに始まるので、t−PAの濃度は保持され、生体内と同等 あるいは非常に近い状態にある。血栓より末梢に流れた血液に直ちに抗凝血薬を 添加することにより、この血液を全試験期間にわたって、抗凝血薬を含み、稀釈 されて血液細胞を含まないものとすると、血栓に対し平均して十分な圧力がかか ることを保証している。すなわち結果として、生体内の状態を正確に再現してい ることになる。The clot whose time to disintegration should be measured should be a single, distinct, physiologically relevant blood clot. By stimulation, i.e. hemodynamic pressure (shear force, 5hear force) , made from blood without anticoagulants. This clot is strong enough to approximate arterial blood pressure They withstand pressure and do not pull apart, but rather collapse on their own. Blood clot formation Since t-PA concentration begins immediately after starting the blood sample, the concentration of t-PA is maintained and is equivalent to that in vivo. Or very close. Immediately administer anticoagulants to blood that flows from the thrombus to the periphery. This blood is kept diluted and contains anticoagulants for the entire duration of the study by adding Assuming that the blood clot contains no blood cells, sufficient pressure is exerted on average against the thrombus. We guarantee that In other words, as a result, the in-vivo conditions are accurately reproduced. That will happen.
また、この試験は容易に自動化でき、特に多系統用装置を用いれば、多数の患者 の検査を、最小の人員で、比較的短時間に実施することができる。Additionally, this test can be easily automated, especially with multisystem equipment, to test large numbers of patients. inspections can be carried out in a relatively short time with a minimum number of personnel.
国際調査報告 。1.T/I’!O07,。77.。International search report. 1. T/I'! O07,. 77. .
フロントページの続き (81)指定国 EP(AT、BE、CH,DE。Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.
DK、ES、FR,GB、GR,IE、IT、LU、MC,NL、 PT、 S E)、CA(BF、BJ、CF、CG、 CI、 CM、 GA、 GN、 M L、 MR,SN、 TD。DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, S E), CA (BF, BJ, CF, CG, CI, CM, GA, GN, M L, MR, SN, TD.
TG)、 AT、 AU、 BB、 BG、 BR,CA、 CH。TG), AT, AU, BB, BG, BR, CA, CH.
C3,DE、DK、ES、FI、GB、HU、JP、KP、KR,LK、LU、 MG、MN、MW、NL、N。C3, DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, N.
、 NZ、 PL、 PT、 RO,RU、 SD、 SE、 UA。, NZ, PL, PT, RO, RU, SD, SE, UA.
SS
Claims (15)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9126987.8 | 1991-12-19 | ||
GB919126987A GB9126987D0 (en) | 1991-12-19 | 1991-12-19 | Improvements in and relating to blood measurements |
PCT/GB1992/002328 WO1993012423A1 (en) | 1991-12-19 | 1992-12-16 | Measurement of the thrombolytic activity of blood |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH06505567A true JPH06505567A (en) | 1994-06-23 |
JP3135574B2 JP3135574B2 (en) | 2001-02-19 |
Family
ID=10706540
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP05510742A Expired - Fee Related JP3135574B2 (en) | 1991-12-19 | 1992-12-16 | Blood thrombolytic activity measurement method |
Country Status (7)
Country | Link |
---|---|
US (1) | US5599718A (en) |
EP (1) | EP0575576B1 (en) |
JP (1) | JP3135574B2 (en) |
AU (1) | AU3164893A (en) |
DE (1) | DE69221857T2 (en) |
GB (1) | GB9126987D0 (en) |
WO (1) | WO1993012423A1 (en) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU5896198A (en) * | 1996-12-20 | 1998-07-17 | Xylum Corporation | Thrombotic and/or thrombolytic status analyser |
US7745106B2 (en) * | 1997-06-24 | 2010-06-29 | Cascade Medical Enterprises, Llc | Methods and devices for separating liquid components |
US6979307B2 (en) * | 1997-06-24 | 2005-12-27 | Cascade Medical Enterprises Llc | Systems and methods for preparing autologous fibrin glue |
US6016712A (en) * | 1997-09-18 | 2000-01-25 | Accumetrics | Device for receiving and processing a sample |
SE515423C2 (en) * | 1998-02-06 | 2001-07-30 | Boule Medical Ab | Method and apparatus for diluting a blood sample |
DE19939252A1 (en) * | 1999-08-16 | 2001-04-19 | Volker Goltz | Apparatus for testing blood samples has a reaction vessel with limited surfaces forming a reaction zone for blood platelets to adhere to a reaction surface for reactions to be examined |
DE10003093C2 (en) * | 2000-01-25 | 2002-05-16 | Goltz Volker Freiherr Von | Device for investigating properties of the global hemostasis function in whole blood or platelet-rich plasma |
EP1546710A4 (en) * | 2002-09-10 | 2011-05-25 | Placor Inc | Method and device for monitoring platelet function |
US6881588B2 (en) * | 2002-10-18 | 2005-04-19 | Indiana University Research & Technology Corporation | Fluid treatment device |
US7422905B2 (en) * | 2004-02-27 | 2008-09-09 | Medtronic, Inc. | Blood coagulation test cartridge, system, and method |
US7439069B2 (en) * | 2004-02-27 | 2008-10-21 | Nippoldt Douglas D | Blood coagulation test cartridge, system, and method |
US7399637B2 (en) * | 2004-04-19 | 2008-07-15 | Medtronic, Inc. | Blood coagulation test cartridge, system, and method |
WO2006116361A2 (en) * | 2005-04-25 | 2006-11-02 | Placor Inc. | Methods and devices for monitoring platelet function |
US20070037271A1 (en) * | 2005-08-15 | 2007-02-15 | Jang-Chi Huang | Vitrification apparatus for microdrop vitrification of cells and a method of microdrop vitrification of cells using the apparatus |
US20100099130A1 (en) * | 2006-10-25 | 2010-04-22 | Placor Inc. | Methods and devices for monitoring platelet function |
KR101317215B1 (en) * | 2010-02-11 | 2013-10-15 | 동국대학교 산학협력단 | Measuring methods for thrombolysis and thrombolytic resistance customized to individual patients |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2218803A5 (en) * | 1973-02-19 | 1974-09-13 | Daillet Ets | |
DE3247815C2 (en) * | 1982-12-23 | 1985-10-17 | Gustav Viktor Rudolf Prof. London Born | Device for measuring the bleeding time in vitro |
GB8316332D0 (en) * | 1983-06-15 | 1983-07-20 | Gorog P | Measuring haemotasis |
DE3541057A1 (en) * | 1985-11-19 | 1987-05-21 | Kratzer Michael | METHOD AND DEVICE FOR MEASURING THE AGGREGATION OF BLOOD PLATES OR THE COAGULATION OF THE BLOOD |
DE3739247C2 (en) * | 1987-11-19 | 1996-11-21 | Dade Int Inc | Bleeding time measuring device |
US4867069A (en) * | 1988-04-01 | 1989-09-19 | Zygmunt Alexander Kunczynski | Transportation system drive-shoe assembly and method |
US4952373A (en) * | 1989-04-21 | 1990-08-28 | Biotrack, Inc. | Liquid shield for cartridge |
US5207988A (en) * | 1989-07-06 | 1993-05-04 | The Cleveland Clinic Foundation | Apparatus for detecting and quantifying clot lysis and establishing optimum medication and dosages |
US5047211A (en) * | 1989-08-18 | 1991-09-10 | Xylum Corporation | Disposable blood handling cassette device for measuring haemostasis |
US5296379A (en) * | 1990-03-23 | 1994-03-22 | Peter Gorog | Apparatus and method for modeling arterial thrombus formations |
US5293772A (en) * | 1992-01-17 | 1994-03-15 | Center For Innovative Technology | Instrumentation and method for evaluating platelet performance during clotting and dissolution of blood clots and for evaluating erythrocyte flexibility |
-
1991
- 1991-12-19 GB GB919126987A patent/GB9126987D0/en active Pending
-
1992
- 1992-12-16 EP EP93900279A patent/EP0575576B1/en not_active Expired - Lifetime
- 1992-12-16 JP JP05510742A patent/JP3135574B2/en not_active Expired - Fee Related
- 1992-12-16 WO PCT/GB1992/002328 patent/WO1993012423A1/en active IP Right Grant
- 1992-12-16 DE DE69221857T patent/DE69221857T2/en not_active Expired - Fee Related
- 1992-12-16 US US08/107,672 patent/US5599718A/en not_active Expired - Fee Related
- 1992-12-16 AU AU31648/93A patent/AU3164893A/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
DE69221857T2 (en) | 1998-03-19 |
DE69221857D1 (en) | 1997-10-02 |
US5599718A (en) | 1997-02-04 |
EP0575576A1 (en) | 1993-12-29 |
WO1993012423A1 (en) | 1993-06-24 |
GB9126987D0 (en) | 1992-02-19 |
AU3164893A (en) | 1993-07-19 |
JP3135574B2 (en) | 2001-02-19 |
EP0575576B1 (en) | 1997-08-27 |
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LAPS | Cancellation because of no payment of annual fees |